Cigarette smoking's effects are different in men vs. women. Men experience greater reinforcement and reward from the nicotine whereas women tend to smoke for stress and affect regulation. Studies report that nicotine replacement therapy (NRT) is more effective for smoking cessation in men. Understanding sex- differences in the neurochemical mechanisms underlying treatment efficacy and smoking behavior will help drive gender-sensitive treatment development. Innovation: We will use PET imaging, a novel experiment that includes smoking in the scanner, and analysis that captures temporal information to detect sex-differences in the brain's dopamine (DA) response to smoking a cigarette. To date, PET imaging studies of smoking have been hampered by suboptimal experimental designs or inadequate models of the data. We fill the knowledge gap in design with high resolution scanning and high frequency motion correction. We fill the gap in analysis with our innovative model, lp- ntPET, that specifically accounts for short-lived and time-varying DA activation caused by smoking. Preliminary Findings: Thanks to our new methods, we recently discovered that men activate DA transmission in right ventral striatum when smoking but women do not. We also identified distinct areas in dorsal striatum where women activate DA faster than men while smoking. These preliminary data provide insight into the potential biological bases for established behavioral sex differences. Approach: Aims (1, 2): To examine large cohorts of men and women smoking in order to identify sex- differences in location, spatial extent, and timing of DA release due to smoking. Aim (3): To measure sex- differences in the effect of NRT for smoking cessation on the DA system. Aim (4): To examine the effect of Chantix on DA timing as an explanation of its unique mechanism of action. Further aims seek to relate the location and temporal patterns of DA release (generated by our novel methods) to individual behaviors during smoking (e.g., craving) and to clinical measures (e.g., dependence). In this way, we will uncover mechanisms of action of medications and establish new image-based, spatiotemporal biomarkers of addiction Key elements. PET will be conducted with the D2 antagonist tracer, 11C-raclopride. Smokers will smoke cigarettes inside a high-resolution brain scanner equipped with high-frequency head-motion detection. Smokers will be scanned after 1 week of medication (NRT or Chantix) and after 1 week of placebo control. All will be blinded and order will be randomized. lpntPET is a novel model for dynamic PET data, developed by the investigators, for capturing DA kinetics at the voxel level. The methods are novel but validated and uniquely suited to discover the neurochemical bases of sex-differences in response to smoking and medications for smoking cessation.